The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma
| Autor: | Jie Wang, Rutong Yu, Chenglong Yue, Mingshan Niu, Qiyu Cao, Xiangyu Chen, Shangfeng Gao, Shengsheng Li, Lin Shi, Qianqian Shan, Huan Li, Xuejiao Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Cell cycle checkpoint urologic and male genital diseases Mice 0302 clinical medicine Cell Movement Epidermal growth factor receptor Cell proliferation EGFR inhibitors Aniline Compounds biology Brain Neoplasms lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens female genital diseases and pregnancy complications ErbB Receptors Oncology 030220 oncology & carcinogenesis EGFR/ERK signaling pathway Erlotinib medicine.drug Cell Survival MAP Kinase Signaling System Brain tumor AZD9291 GBM lcsh:RC254-282 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans Protein Kinase Inhibitors Acrylamides Dose-Response Relationship Drug Cell growth business.industry urogenital system Research medicine.disease Xenograft Model Antitumor Assays nervous system diseases 030104 developmental biology Drug Resistance Neoplasm Apoptosis Cancer research biology.protein Glioblastoma business |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-14 (2019) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| Popis: | Background Glioblastoma (GBM) is a fatal brain tumor, lacking effective treatment. Epidermal growth factor receptor (EGFR) is recognized as an attractive target for GBM treatment. However, GBMs have very poor responses to the first- and second-generation EGFR inhibitors. The third-generation EGFR-targeted drug, AZD9291, is a novel and irreversible inhibitor. It is noteworthy that AZD9291 shows excellent blood–brain barrier penetration and has potential for the treatment of brain tumors. Methods In this study, we evaluated the anti-tumor activity and effectiveness of AZD9291 in a preclinical GBM model. Results AZD9291 showed dose-responsive growth inhibitory activity against six GBM cell lines. Importantly, AZD9291 inhibited GBM cell proliferation > 10 times more efficiently than the first-generation EGFR inhibitors. AZD9291 induced GBM cell cycle arrest and significantly inhibited colony formation, migration, and invasion of GBM cells. In an orthotopic GBM model, AZD9291 treatment significantly inhibited tumor survival and prolonged animal survival. The underlying anti-GBM mechanism of AZD9291 was shown to be different from that of the first-generation EGFR inhibitors. In contrast to erlotinib, AZD9291 continuously and efficiently inhibited the EGFR/ERK signaling in GBM cells. Conclusion AZD9291 demonstrated an efficient preclinical activity in GBM in vitro and in vivo models. AZD9291 has been approved for the treatment of lung cancer with good safety and tolerability. Our results support the possibility of conducting clinical trials of anti-GBM therapy using AZD9291. Electronic supplementary material The online version of this article (10.1186/s13046-019-1235-7) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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